Project 1: Genetic association and comparative cohort studies Abstract Cardiometabolic diseases (CMD) develop across the lifespan and result from a complex set of interactions that include the environment, behavioral choices, socio-demographic and socio-economic factors, interacting with a genetic susceptibility profile. Africa has a highly diverse group of ethnic populations each with their specific cultural practices, norms and unique environments that have evolved over time. It is therefore important to study multiple groups and one of the strengths of AWI-Gen is our presence in west-east-south Africa, in both rural and urban settings undergoing complex health and demographic transitions. AWI-Gen Phase 1 was a population- based cross-sectional study of ~12,000 individuals to examine genetic and environmental contributions to CMD; the renewal application for AWI-Gen Phase 2 will build from these baselines and establish longitudinal cohorts in Agincourt, Dikgale, Nairobi, Nanoro, Navrongo and Soweto; well-established research settings in rural and urban South Africa, Kenya, Burkina Faso and Ghana. This will make it possible to evaluate genetic associations, genetic susceptibility and gene-environment (G-E) interactions in a diversity of sub-Saharan African populations, notably to look at associations with risk trajectories for cardiometabolic disease over a 5-year period. This will be the first multi-ethnic study in sub-Saharan Africa to address a critical shortfall in understanding at a time when the force of transitions is driving the rise in cardiometabolic conditions. We expect findings to be highly relevant in our continental context and contribute insights far more widely. This project outlines our plans for a second phase of data and sample collection on all AWI-Gen participants. Since the study is nested in established population cohorts of the INDEPTH Network and Developmental Pathways to Health Research Unit (DPHRU), we anticipate a greater than 70% follow-up of the original enrolled participants. This will provide an opportunity to examine changes in CMD relevant biomarkers (including blood pressure, lipid profiles, fasting blood glucose and insulin levels), body composition (including visceral and subcutaneous fat) and health-related behaviors (smoking, alcohol consumption and physical activity). We will also have comprehensive data on all deaths occurring and their probable cause among those in the original cohorts, and thus be in a unique position to formulate risk prediction models in African settings that incorporate genomic understanding as well as established risk markers. Genome-wide SNP array data will be available from Phase 1 and used for association and G-E interaction studies. Replication of risk loci which transfer from European and other populations to Africans will create a unique potential to harness the lower levels of linkage disequilibrium in African genomes for fine mapping of these loci to causal genes and variants, and will guide fine mapping and functional analysis in candidate regions, including regional capture next generation sequencing. We will also pursue in-depth analysis of outlier CMD phenotypes such as individuals with a persistent ?Metabolically Healthy Obese? (MHO) phenotype and potential low frequency high impact alleles. Our overall goal is to establish the genomic contribution to cardiometabolic diseases and risk at a time when multiple interacting transitions, in the presence of high background infectious disease prevalence, are driving a rapid escalation in CMD across the African continent. Given rising life expectancy, additional questions and measurements related to aging and cognition will be included so as to harmonize with the NIH-supported Health & Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI) project underway at Agincourt. The approach for AWI-Gen Phase 2 will require enhanced community engagement and we envisage an effective strategy for feedback of results to individuals and communities.